A Phase I Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Dopamine D1 Receptor Partial Agonist, PF-06669571, in Subjects with Idiopathic Parkinson’s Disease

Abstract

Background and Objectives

There is an unmet medical need for additional treatment options for Parkinson’s disease. This was a Phase I, double-blind clinical trial assessing safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of the novel dopamine D1 receptor partial agonist, PF-06669571, in subjects with idiopathic Parkinson’s disease on a stable dose of l-DOPA.

Methods

Subjects received PF-06669571 (or matching placebo) titrated from 1 mg to 3 mg over 7 days. The primary pharmacodynamic endpoint was the change from baseline in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale Part III total motor score at the pharmacodynamic time of maximum change from baseline on day 7.

Results

Twenty subjects were randomized and 19 completed the study. Maximum plasma concentrations (C_max) of PF-06669571 were reached 3.35 and 3.19 h post-dose on day 1 and day 7. Geometric mean C_max and area under the plasma concentration–time profile from time 0 to 24 h post-dose on day 7 were 92.51 ng/mL and 1626 ng·h/mL, respectively. The primary pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement; however, the criteria were met in a sensitivity analysis excluding data from a l-DOPA outlier (l-DOPA dose of 2550 mg/d). The most common adverse events (AEs) were nausea (experienced by 2 subjects each in the PF-06669571 and placebo groups). There were no permanent discontinuations or dose reductions due to AEs.

Discussion

Multiple daily doses of PF-06669571 were safe and well tolerated with no notable safety concerns. The pharmacodynamic endpoint did not meet the pre-specified criteria for significant improvement.

Clinicaltrials.gov identifier

NCT02565628.

Appendix

1.1 List of Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs)

*1011 Quorum Review IRB, 1501 Fourth Ave, Ste 800, Seattle, WA 98101, UNITED STATES.

*IRB for 6 study sites.

1016 IntegReview Ethical Review Board, 3815 S. Capital of Texas Hwy, Ste 320, Austin, TX 78704, UNITED STATES.

1.2 Exploratory Endpoints

1.2.1 Hopkins Verbal Learning Test-Revised (HVLT-R)

The HVLT–R™ is a word-list learning and memory test that was used in this study to assess changes in memory. It is very brief, easy to administer, and well tolerated. The test is available in 6 forms that are very similar in their psychometric properties. Each form of the HVLT-R consists of a list of 12 nouns, with 4 items drawn from each of 3 semantic categories. The specific semantic categories vary across the 6 forms.

A list was read to the respondent, who then attempted to recall as many words as possible, in any order. The examiner recorded each response verbatim, including intrusions and repetitions. This task was repeated 2 more times, for a total of 3 learning trials. After a delay interval of 20–25 min, a delayed recall trial was administered.

Learning efficiency can have been assessed by examining the learning curve over the 3 learning trials and by evaluating the sum of the scores for all 3 learning trials. Ability to access newly learned information was assessed by the number of words retained on the delayed recall trial and the percentage of words recalled from the word list.

Raw scores for each of the 3 Learning Trials were summed for the Total Recall score. The Total Recall score ranged from 0-36 while the Delayed Recall Trial score ranged from 0-12. On this assessment, higher scores indicated greater verbal learning and recall. Raw scores could have been converted to T scores by consulting the appropriate normative data tables included in the instrument manual.

Two (2) HVLT-R endpoints were evaluated: change from baseline for the raw total recall score and change from baseline for the raw delayed recall trial score. Baseline was defined as the day 0 assessment.

1.2.2 Apathy Evaluation Scale-Self Report (AES-S)

AES-S consists of 18 items. Each item is anchored with 4 responses: 0 to 3 (0 = Not at all, 3 = A lot). Total score ranges from 0 to 54. AES-S endpoint was the change from baseline measurement of the AES-S total score. Baseline was defined as the day 0 assessment.

1.2.3 Trail Making Test Parts A and B (TMT)

This test provides an assessment of executive function. This test measured the time the subject takes to connect a sequence of numbers (Trails Part A) and a sequence of alternating numbers and letters (Trails Part B). An incorrect sequence was considered an error and time limit for completion was 5 minutes.

Results for both TMT A and B are reported as the number of seconds required to complete the task. Higher scores represent greater impairment.

The TMT endpoint was a change from baseline measurement. Baseline was defined as the Day 0 assessment.

1.2.4 Digit Span

Digit span is an assessment of working memory and attention in which the subject was presented a series of digits and was asked to repeat them back in the same order. The other part of this assessment entailed asking the subject to repeat the series of digits backwards. In both cases, the subject was presented with an even longer list of numbers with each correct response and the assessment ended with an incorrect response. The longest series of digits that a subject could have repeated was the subject’s digit span and this was recorded for both forward and backward span.

The digit span endpoint was a change from baseline measurement. Baseline was defined as the Day 0 assessment.

1.2.5 Snaith Hamilton Pleasure Scale (SHAPS)-Anhedonia

SHAPS consists of 14 items covering 4 domains of pleasure response (social interaction, food and drink, sensory experience, achievement and past times). Subjects were instructed to indicate the degree to which each item caused them pleasure on a 4-point scale: 0 to 3 (0 = strongly disagree, 3 = strongly agree). Total score ranges from 0 to 42.

The SHAPS endpoint was the change from baseline measurement of the SHAPS total score. Baseline was defined as the day 0 assessment.